Rensen P C, de Vrueh R L, van Berkel T J
Division of Biopharmaceutics, Leiden-Amsterdam Center for Drug Research, University of Leiden, Sylvius Laboratories, The Netherlands.
Clin Pharmacokinet. 1996 Aug;31(2):131-55. doi: 10.2165/00003088-199631020-00005.
The hepatitis B virus (HBV) is the world's most important chronic virus infection. The immunomodulator interferon-alpha (IFN alpha) is the only clinically applied drug available, despite its low response rate (approximately 30%) even in highly selected chronic carriers. Antiviral nucleoside analogues have proven to be potent inhibitors of viral replication in vitro, but their significant adverse effects which are, at least partially, due to their nonspecific body distribution, have forced the cessation of their clinical development in the past. For example, vidarabine causes severe neuromuscular toxicity, and fialuridine has caused fatal cases of liver and kidney failure in a recent clinical trial. Furthermore, the potential clinical application of (modified) antisense oligodeoxynucleotides, which are very specific inhibitors of viral replication, is hampered by their nonspecific body distribution, instability in serum and poor cell penetration. As infection and replication of HBV mainly occur in liver parenchymal cells, selective targeting of antiviral nucleoside analogues as well as antisense oligodeoxynucleotides to the liver would theoretically improve therapeutic efficacy. At present, conjugates of vidarabine and neoglycoproteins have entered clinical trials, and initial data suggest that therapeutic concentrations are achieved at lower dosages with minor adverse effects. These data have stimulated preclinical research on other liver-specific drug carriers for the selective delivery of HBV-active drugs such as glycosylated polymers and neolipoproteins: these approaches are outlined in this paper.
乙型肝炎病毒（HBV）是全球最重要的慢性病毒感染源。免疫调节剂α干扰素（IFNα）是唯一可临床应用的药物，即便在经过高度筛选的慢性携带者中其应答率也很低（约30%）。抗病毒核苷类似物在体外已被证明是强效的病毒复制抑制剂，但由于其非特异性的体内分布导致的显著不良反应，使得过去它们的临床开发被迫中止。例如，阿糖腺苷会引起严重的神经肌肉毒性，在最近的一项临床试验中，氟尿苷导致了致命的肝肾功能衰竭病例。此外，（修饰的）反义寡脱氧核苷酸作为非常特异的病毒复制抑制剂，其潜在的临床应用受到非特异性体内分布、血清中不稳定以及细胞穿透性差的阻碍。由于HBV的感染和复制主要发生在肝实质细胞中，理论上，将抗病毒核苷类似物以及反义寡脱氧核苷酸选择性靶向肝脏可提高治疗效果。目前，阿糖腺苷与新糖蛋白的缀合物已进入临床试验，初步数据表明较低剂量即可达到治疗浓度且不良反应较小。这些数据推动了针对其他肝脏特异性药物载体的临床前研究，以选择性递送具有抗HBV活性的药物，如糖基化聚合物和新脂蛋白：本文将概述这些方法。
